The Ahr knockout mouse allows us to answer many questions about the mechanisms by which TCDD induces toxicity and potentiates carcinogenicity. Further, this animal will give us great insight to the endogenous function of the AHR. This insight will likely provide us with new ways to understand the toxicology of TCDD. However, apparent differences in the phenotypes of two independently derived Ahr knockout mice obfuscate studies of the AHR. Disparate phenotypes between the Ahr null mice may result from variations in investigator protocol, environmental or genetic background, or targeting strategy. We propose to examine both Ahr null mice under identical environmental and genetic contexts to determine if the phenotypes remain different. If differences remain, then we will examine the effects of different targeting strategies on expression of the targeted allele and adjacent loci. As we reconcile differences between null animals, we will also examine variables that may affect their phenotypes, such as pathogen and pollutant exposure, with the hopes of identifying genes that modify responses to the targeted Ahr allele. Finally, we will pursue two endpoints, neonatal survival of null mice and liver size, to unravel some of the interactions between the Ahr and other mouse genes. It is hoped that through this work, we will gain much greater understanding of the interactions of the AHR with other gene products and thus identify other susceptibility genes for TCDD-induced toxicity and cancer potentiation.